The techniques of cell and molecular biology are used to analyze mechanisms which control the expression of differentiated genes in normal and leukemic hematopoietic cells. A chromosomal-dependent APRT-specific method of interspecies transfer of the human alpha globin gene (HAGG) has been developed. Using this method, we have isolated mouse erythroleukemia hybrid cells in which retention at high or low frequency of the HAGG occurs. Full expression and stable retention of this gene are observed when the human donor cell is of erythroid origin. Transcription of the HAGG without translation to globin chains occurs when the donor cell is a human peripheral blood leukocyte. We are attempting to elucidate the mechanism of this control as well as to identify other types of regulation. Study of a hybrid derived by fusion of a rodent erythroleukemia cell with a human promyelocytic leukemia cell has led to the conclusion that maintenance of myeloid differentiation in the hybrids is dependent on the presence of a ploidy excess of chromosomes of myeloid origin. Such hybrids are being studied to clarify further the defect in human leukemic hematopoietic cells which leads to the accumulation of immature but committed myeloid precursor cells (blasts).